This is a revised competitive renewal application of a project based on our discovery of abeneficial role for the peripheral immune system in mouse facial motoneuron (FMN)reparative processes. In the initial funding period, the immune cellular and molecular components involved were identified:the CD4+ effector Th2 cell is necessary for FMN survival after facial nerve injury, via an antigen-dependent process requiring peripheral activation and central re-activation. & brain-derived neurotrophic factor (BDNF) is an essential molecule. Importantly, FACS analysis of lymph node cells taken from axotomized mice indicates that Thi/Th2 cytokine-secreting cells are generated in response to peripheral nerve injury. Functional recovery from facial paralysis induced by crush injury is impaired in immunodeficient mice, but can be restored to wildtype (WT) with immune reconstitution. It is hypothesizedthat CD4+effector T cells play distinct roles in motoneuron reparative processes, with the Tha cell mediating FMN survival through a central BDNF-dependent process and the Thi cell mediating functional recovery byparticipation in the lesion site pro-inflammatory response. 4 aims will test this hypothesis. Aim #1 is to determine the mechanism underlying CD4+ effector T cell localization within the facial motor nucleus after facial nerve injury. Experiments will utilize immunodeficient mice reconstituted with GFP-expressing CD4+Tcells, in sifu hybridization with Thi/Th2 cytokine riboprobes, chemokine RT- PCR, and chemokine neutralization antibodies/knockout mice. Aim #2.is to determine the mechanism underlying CD4+ T cell-mediated FMNsurvival after facial nerve injury, and will use WT and chimeric BDNF-negative mice to test the role of CD4+T cell-derived BDNF in FMNrescue. Aim #3 is to determineif immune cell-mediated rescue of cranial motoneurons (FMN)from axotomy-induced cell death can be generalized to a spinal MN. WT,immunodeficient,and reconstituted immunodeficientmicewill be used to determine the impact ofthe immune system on sciatic MNviability after sciatic nerve injury. Aim #4 is to determine if the Thi effector cell mediates functionalrecoveryfrom peripheral nerveinjury-induced paralysis. STAT4,T-bet, and STAT6deficient mice will be used with selective reconstitution experiments to determine the role of Thi/Th.2 effector cells in recovery of motor function, assessed with behavioral tests, after a facial or sciatic nerve crush injury. The immune system can have both protective and destructive effects in neural disease (such as amyotrophic lateral sclerosis, a fatal MNdisease) and/or trauma (such as spinal cord injury), but the regulatory nature ofsuch contradictory actions has yet to be determined. Understanding how the immune system benefits the injured nervous system holds great promise in the development of effective treatment strategies to offset disease or injury progression, and reduce disability.